The mission of this research program is to apply our expertise in organic chemistry to the design and synthesis of novel anti-tubercular, antibiotic, anticancer, and steroid-based drug candidates. Each of the scientific aims of this program will seek chemical innovation in the pursuit of high profile, natural product-based targets. In Aim I, we will develop a transformative new strategy for achieving rapid and flexible syntheses of diverse collections of steroid-based pharmaceutical candidates from simple precursor fragments. Our approach is designed to provide access to many new varieties of steroids, incorporating substitution patterns that have not yet been explored in biological research. The goal of Aim II is to respond to the rising threat to public health caused by multidrug resistant strains of Mycobacterium tuberculosis and the alarming lack of new antibiotic drug candidates. Through thoughtful molecular design and chemical synthesis, we will invent new candidates for antibiotic and antitubercular drug development efforts based on the tricyclic architecture that defines the pleuromutilin class of bacterial protein synthesis inhibitors. Notably, these candidates will be engineered to exhibit enhanced metabolic stability compared to the currently known members of the pleuromutilin family. We will probe the stability, antitubercular activity, and broad-spectrum antibiotic activity of our new pleuromutilin-based compounds through research collaborations. In Aim III of this proposal, we will complete a short and innovative synthesis of the high profile natural product, maoecrystal V. Isolated in 2004, maoecrystal V has attracted significant attention from the biomedical community due to reports of its potent and selective cytotoxic activity against cervical cancer cells. We propose herein to employ the concepts and methods of chemical synthesis to gain access to significant quantities of the natural product for collaborative studies directed toward the elucidation of the mechanism of action of maoecrystal V. Our design for synthesis will also open new avenues by which to access structurally novel screening candidates incorporating key elements of the structure of maoecrystal V. PUBLIC HEALTH RELEVANCE: Advances in chemical synthesis enable the design and production of structurally unique molecules that selectively modulate biological processes and have great potential as molecular therapeutics for the treatment of human diseases. Through innovative advances in chemical synthesis, this research program will create new antibiotic, anti-tubercular, anticancer, and steroid-based candidates for drug development efforts. The power of the approaches described herein lie in their ability to create not only known therapeutic agents, but also novel, specifically modified molecules with improved therapeutic properties.